The World Health Organization has recently labeled obesity as one of the top global health problems. One of the primary reasons for the increase in chronic kidney disease is the increase in obesity related type 2 diabetes and its co-existence with hypertension. The clustering of cardiovascular risk factors such as inflammation, endothelial dysfunction and insulin resistance are intertwined in obesity and hypertension. This triad of risk factors is largely responsible for the progression of chronic kidney disease in obesity and hypertension or what is now known as Cardiometabolic Syndrome. TNF- is an important cytokine secreted by adipose tissue that can increase cardiovascular risk and end organ damage in obesity. We have recently demonstrated that TNF- can decrease Cyp2c derived epoxyeicosatrienoic acids (EETs). These Cyp2c derived epoxyeicosanoids have renal and cardiovascular protective properties. A signaling pathway that could possible link TNF- and epoxides to endothelial dysfunction and renal damage is NFB activation of cell adhesion molecules such as MCP-1. The contribution of TNF-, epoxyeicosanoids, and NFB to the progression of chronic kidney disease in obesity and hypertension has not been elucidated. Therefore, we will test the hypothesis that increased TNF- , decreased epoxides and increased MCP-1 contribute to renal vascular injury in obesity and hypertension. We will determine the effects of high fat diet induced obesity on afferent arteriolar function, blood pressure and renal injury in hypertensive animals. The current proposal will define the contribution of TNF-, EETs, NFB and MCP-1 and interactions between these pathways in obesity and hypertension. This proposal incorporates novel metabolic oxylipid profiling, RT-PCR arrays and targeted analysis of cellular mechanisms that will allow for unique insight concerning mechanisms that contribute to the progression of kidney disease in obesity and hypertension. Collectively, the proposed experiments in this application will provide novel mechanistic insight on the progression of chronic kidney disease in obesity and hypertension. Project Narrative: The World Health Organization has recently labeled obesity as one of the top global health issues. One of the primary reasons for the increase in chronic kidney disease is the increase in obesity related diabetes and its co- existence with hypertension. This project will test the hypothesis that interactions between fatty acid metabolites and inflammatory molecules accelerate the progression of chronic kidney disease in obesity and hypertension. On the whole, the proposed experiments in this application will provide novel insight and therapeutic targets for the treatment of chronic kidney disease in obesity and hypertension.